CD4+ T Cells Drive Goblet Cell Depletion during Citrobacter rodentium Infection
CD4+ T Cells Drive Goblet Cell Depletion during Citrobacter rodentium Infection
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DOI：
10.1128/iai.00655-13
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发表时间：
2013-12-01
影响因子：
3.1
通讯作者：
Vallance, Bruce A.
中科院分区：
文献类型：
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作者：
Chan, Justin M.;Bhinder, Ganive;Vallance, Bruce A.
特发性和感染性结肠炎都会破坏正常的肠上皮细胞（IEC）增殖和分化，但其机制仍不清楚。最近，我们证明，附着和消除鼠类病原体啮齿类柠檬酸杆菌的感染会导致结肠杯状细胞数量显着减少（杯状细胞耗竭）。这种病理学依赖于 T 和/或 B 细胞，因为 Rag1(-/-) 小鼠在感染期间不会遭受这种耗竭，而是遭受高死亡率。为了解决所涉及的免疫机制，我们用 CD4(+) 或 CD8(+) T 细胞重建了 Rag(-/-) 小鼠。两种T细胞亚群都增加了Rag1(-/-)小鼠在感染期间的存活率，接受CD8(+)T细胞的小鼠出现结肠溃疡，但没有出现杯状细胞耗竭。相比之下，接受CD4(+) T细胞的小鼠表现出杯状细胞耗竭以及过度的IEC增殖。为了确定 T 细胞衍生细胞因子的可能参与，我们感染了 γ 干扰素受体基因敲除 (IFN-γ R-/-) 小鼠和给予白细胞介素 17A (IL-17A) 中和抗体的野生型小鼠，发现 IFN-γ 信号传导对于杯状细胞耗竭和 IEC 增殖增加都是必需的。免疫染色显示，啮齿类动物 C. rodentium 细胞优先定位于含有大量杯状细胞的非增生性隐窝，而增生性、杯状细胞耗尽的隐窝似乎免受感染。为了解决杯状细胞耗竭是否有益于啮齿类动物感染的宿主，我们使用γ-分泌酶抑制剂二苯并氮杂卓（DBZ）增加了杯状细胞数量，这导致病原体负担和死亡率大大增加。这些结果表明，杯状细胞耗竭反映了 IEC 稳态的宿主免疫调节，并反映了针对粘膜粘附病原体的新型宿主防御机制。
Both idiopathic and infectious forms of colitis disrupt normal intestinal epithelial cell (IEC) proliferation and differentiation, although the mechanisms involved remain unclear. Recently, we demonstrated that infection by the attaching and effacing murine pathogen Citrobacter rodentium leads to a significant reduction in colonic goblet cell numbers (goblet cell depletion). This pathology depends on T and/or B cells, as Rag1(-/-) mice do not suffer this depletion during infection, instead suffering high mortality rates. To address the immune mechanisms involved, we reconstituted Rag(-/-) mice with either CD4(+) or CD8(+) T cells. Both T cell subsets increased Rag1(-/-) mouse survival during infection, with mice that received CD8(+) T cells developing colonic ulcers but not goblet cell depletion. In contrast, mice that received CD4(+) T cells showed goblet cell depletion in concert with exaggerated IEC proliferation. To define the possible involvement of T cell-derived cytokines, we infected gamma interferon receptor gene knockout (IFN-gamma R-/-) mice and wild-type mice given interleukin 17A (IL-17A) neutralizing antibodies and found that IFN-gamma signaling was required for both goblet cell depletion and increased IEC proliferation. Immunostaining revealed that C. rodentium cells preferentially localized to nonhyperplastic crypts containing numerous goblet cells, whereas hyperplastic, goblet cell-depleted crypts appeared protected from infection. To address whether goblet cell depletion benefits the C. rodentium-infected host, we increased goblet cell numbers using the gamma-secretase inhibitor dibenzazepine (DBZ), which resulted in greatly increased pathogen burdens and mortality rates. These results demonstrate that goblet cell depletion reflects host immunomodulation of IEC homeostasis and reflects a novel host defense mechanism against mucosal-adherent pathogens.